Temporal trend and risk determinants of hepatocellular carcinoma in chronic hepatitis B patients on entecavir or tenofovir
Yao-Chun Hsu
School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan
Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
Search for more papers by this authorHsiu-J. Ho
Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
Search for more papers by this authorTeng-Yu Lee
Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
Search for more papers by this authorYen-Tsung Huang
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
Departments of Epidemiology and Biostatistics, Brown University, Providence, RI, USA
Search for more papers by this authorMing-Shiang Wu
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorJaw-Town Lin
School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan
Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
Search for more papers by this authorCorresponding Author
Chun-Ying Wu
Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
Correspondence
Chun-Ying Wu, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
and
Hashem B. El-Serag, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Hashem B. El-Serag
Section of Gastroenterology and Hepatology, Department of Medicine, Michael E DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX, USA
Correspondence
Chun-Ying Wu, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
and
Hashem B. El-Serag, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA.
Email: [email protected]
Search for more papers by this authorYao-Chun Hsu
School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan
Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
Search for more papers by this authorHsiu-J. Ho
Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
Search for more papers by this authorTeng-Yu Lee
Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
Search for more papers by this authorYen-Tsung Huang
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
Departments of Epidemiology and Biostatistics, Brown University, Providence, RI, USA
Search for more papers by this authorMing-Shiang Wu
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorJaw-Town Lin
School of Medicine and Big Data Research Center, Fu-Jen Catholic University, New Taipei, Taiwan
Department of Internal Medicine, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
Search for more papers by this authorCorresponding Author
Chun-Ying Wu
Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan
Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
Correspondence
Chun-Ying Wu, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
and
Hashem B. El-Serag, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Hashem B. El-Serag
Section of Gastroenterology and Hepatology, Department of Medicine, Michael E DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX, USA
Correspondence
Chun-Ying Wu, Division of Translational Research, Taipei Veterans General Hospital, Taipei, Taiwan.
Email: [email protected]
and
Hashem B. El-Serag, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA.
Email: [email protected]
Search for more papers by this authorSummary
This study aimed to elucidate the temporal change and determinants for the risk of HCC in patients with chronic hepatitis B continuously receiving NUC. Through analysis of the national healthcare database in Taiwan, we screened a total of 65 426 infected patients receiving entecavir or tenofovir for at least 3 months and excluded those with lamivudine, adefovir or telbivudine exposure, malignancy, end-stage renal failure or a diagnosis of HCC within 3 months of starting treatment. Eligible patients (N = 27 820) were followed until HCC occurrence, completion of the allowed 3-year regimen or 31 December 2013. During a median follow-up of 25.1 (12.1-35.6) months, 802 patients developed HCC, with 1-, 2- and 3-year cumulative incidence of 1.82% (95% CI, 1.66-1.99%), 3.05% (95% CI, 2.82-3.28%) and 4.06% (95% CI, 3.77-4.36%), respectively. HCC annual incidence decreased with an adjusted IRR of 0.73 (95% CI, 0.66-0.80) per yearly interval and was associated with cirrhosis (IRR, 10.07; 95% CI, 6.00-16.90 in age <40 years; 4.69; 95% CI, 3.94-5.59 in age ≧40 years), age (IRR, 3.38; 95% CI, 2.10-5.47 for 40-50 years; 6.92; 95% CI, 4.27-11.21 for 50-60 years; 12.50; 95% CI, 7.71-20.25 for ≧60 years; <40 years as reference), male sex (IRR, 1.71; 95% CI, 1.44-2.04), HCV coinfection (IRR, 1.27; 95% CI, 1.02-1.58) and diabetes (IRR, 1.24; 95% CI, 1.05-1.45). In conclusion, the risk of HCC in patients with chronic hepatitis B receiving entecavir or tenofovir declines over time and is determined by cirrhosis, age, male sex, HCV coinfection and diabetes.
Supporting Information
| Filename | Description |
|---|---|
| jvh12832-sup-0001-SupInfo.docxWord document, 254.3 KB |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012; 142: 1264-73e1.
- 2Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin Gastroenterol Hepatol. 2015; 13: 2140-2151.
- 3Ni YH, Huang LM, Chang MH, et al. Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies. Gastroenterology. 2007; 132: 1287-1293.
- 4Ni YH, Chang MH, Jan CF, et al. Continuing decrease in hepatitis B virus infection 30 years after initiation of infant vaccination program in Taiwan. Clin Gastroenterol Hepatol. 2016; 14: 1324-1330.
- 5Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997; 336: 1855-1859.
- 6Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009; 101: 1348-1355.
- 7Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008; 28: 1067-1077.
- 8Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. J Am Med Assoc. 2012; 308: 1906-1914.
- 9Wu CY, Lin JT, Ho HJ, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology. 2014; 147: 143-151 e5.
- 10Ahn J, Lim JK, Lee HM, et al. Lower observed hepatocellular carcinoma incidence in chronic hepatitis b patients treated with entecavir: results of the ENUMERATE study. Am J Gastroenterol. 2016; 111: 1297-1304.
- 11Lee TY, Lin JT, Zeng YS, Chen YJ, Wu MS, Wu CY. Association between nucleos(t)ide analog and tumor recurrence in hepatitis B virus-related hepatocellular carcinoma after radiofrequency ablation. Hepatology. 2016; 63: 1517-1527.
- 12Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol. 2015; 62: 956-967.
- 13Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol. 2010; 53: 348-356.
- 14Papatheodoridis GV, Dalekos GN, Yurdaydin C, et al. Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir. J Hepatol. 2015; 62: 363-370.
- 15Papatheodoridis G, Dalekos G, Sypsa V, et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol. 2016; 64: 800-806.
- 16Arends P, Sonneveld MJ, Zoutendijk R, et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut. 2015; 64: 1289-1295.
- 17Seo YS, Kim MN, Kim SU, et al. Risk assessment of hepatocellular carcinoma using transient elastography vs. liver biopsy in chronic hepatitis B patients receiving antiviral therapy. Medicine (Baltimore). 2016; 95: e2985.
- 18Kim SS, Hwang JC, Lim SG, Ahn SJ, Cheong JY, Cho SW. Effect of virological response to entecavir on the development of hepatocellular carcinoma in hepatitis B viral cirrhotic patients: comparison between compensated and decompensated cirrhosis. Am J Gastroenterol. 2014; 109: 1223-1233.
- 19Hsu YC, Wu CY, Lane HY, et al. Determinants of hepatocellular carcinoma in cirrhotic patients treated with nucleos(t)ide analogues for chronic hepatitis B. J Antimicrob Chemother. 2014; 69: 1920-1927.
- 20Wong GL, Chan HL, Tse YK, et al. On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir. Hepatology. 2014; 59: 986-995.
- 21Hsu YC. Analyzing Taiwan's National Health Insurance Research Database to explicate the allocation of health-care resources. Adv Dig Med. 2015; 2: 41-42.
- 22Cheng CL, Chien HC, Lee CH, Lin SJ, Yang YH. Validity of in-hospital mortality data among patients with acute myocardial infarction or stroke in National Health Insurance Research Database in Taiwan. Int J Cardiol. 2015; 201: 96-101.
- 23Hsu YC, Lin JT, Chen TT, Wu MS, Wu CY. Long-term risk of recurrent peptic ulcer bleeding in patients with liver cirrhosis: a 10-year nationwide cohort study. Hepatology. 2012; 56: 698-705.
- 24Siegel AB, El-Serag HB. Statins for chemoprevention of hepatocellular carcinoma: assessing the evidence. Expert Rev Gastroenterol Hepatol. 2013; 7: 493-495.
- 25El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009; 136: 1601-1608.
- 26Chen HP, Shieh JJ, Chang CC, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies. Gut. 2013; 62: 606-615.
- 27Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999; 94: 496-509.
- 28Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988; 16: 1141-1154.
- 29Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013; 381: 468-475.
- 30Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010; 52: 886-893.
- 31Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. J Am Med Assoc. 2006; 295: 65-73.
- 32Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002; 347: 168-174.
- 33Liu J, Yang HI, Lee MH, et al. Serum levels of hepatitis B surface antigen and dna can predict inactive carriers with low risk of disease progression. Hepatology. 2016; 64: 381-389.
- 34Hsu YC, Wu CY, Lin JT. Hepatitis C virus infection, antiviral therapy, and risk of hepatocellular carcinoma. Semin Oncol. 2015; 42: 329-338.
- 35Liu CJ, Chu YT, Shau WY, Kuo RN, Chen PJ, Lai MS. Treatment of patients with dual hepatitis C and B by peginterferon alpha and ribavirin reduced risk of hepatocellular carcinoma and mortality. Gut. 2014; 63: 506-514.
- 36Yu ML, Yeh ML, Tsai PC, et al. Huge gap between clinical efficacy and community effectiveness in the treatment of chronic hepatitis C: a nationwide survey in Taiwan. Medicine (Baltimore). 2015; 94: e690.
- 37Wang C, Ji D, Chen J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis c treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017; 15: 132-136.
- 38Collins JM, Raphael KL, Terry C, et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with sofosbuvir and simeprevir. Clin Infect Dis. 2015; 61: 1304-1306.
- 39Huang YT, Yang HI, Liu J, Lee MH, Freeman JR, Chen CJ. Mediation analysis of hepatitis B and C in relation to hepatocellular carcinoma risk. Epidemiology. 2016; 27: 14-20.
- 40El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastro Hepatol. 2006; 4: 369-380.
- 41Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002; 123: 134-140.
- 42McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015; 62: 1148-1155.
- 43El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. Hepatology. 2016; 64: 130-137.
- 44Ono A, Suzuki F, Kawamura Y, et al. Long-term continuous entecavir therapy in nucleos(t)ide-naive chronic hepatitis B patients. J Hepatol. 2012; 57: 508-514.
- 45Kim HS, Kim BK, Kim SU, et al. Association between level of fibrosis, rather than antiviral regimen, and outcomes of patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2016; 14: 1647-56e6.
Citing Literature
